In 2013, there were an estimated 35.3 million people that had been infected and were living with HIV and the number has continued to increase [1]. HIV includes both HIV-1 and HIV-2. Drugs currently used as anti-HIV-1 therapeutics fall under five categories, including inhibitors of viral entry, membrane fusion, the reverse transcriptase, the integrase, and the protease. Highly active anti-retroviral therapy (HAART) combines drugs from at least two of the different classes of the anti-retroviral agents available [2]. Nevertheless, the emergence of drug resistant retroviruses is still a major issue associated with current anti-HIV-1 drug therapies [3]. Hence, the effectiveness of HIV therapy relies on the discovery and approval of novel therapeutics, which are able to combat the various viral replication phases of HIV.
The first anti-retroviral medicine, AZT, was approved in 1987 for the treatment of HIV-1 [4]. This drug terminates DNA strand elongation by the addition of an azide group at the C-3 of the nucleoside sugar. This modification to the 5-carbon sugar is thought to be inspired by the nucleoside analogs produced by the sponge Tethya crypta, that possess an arabinose sugar instead of the deoxyribose sugar required for DNA strand elongation [5]. By substituting the groups bound to the 2′ and 3′ carbons of the nucleoside sugar, a number of HIV-1 reverse transcriptase inhibitors had been generated. This example demonstrates the chemical novelty provided by natural products, which can lead to therapeutic ingenuity. However, the process of finding appropriate natural products can be difficult.
In the past 15 years of clinical trials, it is believed only five novel natural product pharmacophores were investigated in clinical trials. The majority of the 133 naturally derived compounds in clinical trials for the period of 2008-2013 are derivatives of existing pharmacophores that are already present in existing human medicines. For this same time period, only 2 of the 133 compounds, both derivatives of the cyclosporin A pharmacophore, were investigated as anti-viral therapeutic candidates in the treatment of Hepatitis C Virus (HCV) [6]. This reveals that there is a need for novel anti-viral pharmacophores and their derivatives in clinical trials.
A statistical review by Hu et al. [7] illustrates that bioactivities were assigned to only approximately 25% of the marine natural products reported in the literature from 1985-2012. This does not mean that the remaining 75% do not possess bioactivity; instead it suggests a discrepancy between the rate of discovery for marine natural products and the investigation of their associated bioactivities. A further look into the type of bioactivities reported revealed that 56% of the bioactive compounds were associated with anti-cancer activity, but only 3% with anti-viral activity. Interestingly, in years where a greater variety of disease targets were screened in order to identify inhibitors, the proportion of reported bioactivity was the greatest.
This illustrates that there is a need to expand marine natural product screening efforts beyond the detection of anti-cancer activity in order to fully realize the potential utility of marine secondary metabolites.
One Red Sea sponge, Stylissa carteri, is known to produce a number of pharmacologically active brominated pyrrole-2-aminoimidazole alkaloids, which are also produced by sponges from the families Agelasidae, Axindellidae, Hymeniacidonidae [8]. A review of the literature showed that the chemical repertoire of Stylissa sp. is well characterized with nearly 100 compounds reported. Among these compounds, a dimer of oroidin known as sceptrin along with its derivatives debromosceptrin, dibromosceptrin, and oxysceptrin have been reported to inhibit Herpes Simplex Virus-1 (HSV-1) and Vesicular Stomatitis Virus (VSV) [9]. This lends support to the aim of identifying molecules with anti-viral activity from S. carteri. More specific to anti-retroviral activity, another derivative of oroidin, hymenialdisine (HD), has been used experimentally to inhibit Nuclear Factor-kB (NFkB), and subsequently inhibit transcription from the long terminal repeat (LTR) of the Human Immunodeficiency Virus (HIV) in vitro [10].
In a nutshell, while the sponge Stylissa carteri is known to produce a number of secondary metabolites displaying anti-fouling, anti-inflammatory, and anti-cancer activity, the anti-viral potential of metabolites produced by S. carteri has not been extensively explored or reported.
US Patent Publication 2010/0280004 reports that the chemical structures of latonduine A and esters thereof have been described in the reference, Linington et al. (2003) “Latonduines A and B, New Alkaloids Isolated from the Marine Sponge Stylissa carteri: Structure Elucidation, Synthesis, and Biogenetic Implications” Organic Letters, 5: 2735.